title: Greatly increased numbers of histamine cells in human narcolepsy with cataplexy.
abstract: OBJECTIVE
  To determine whether histamine cells are altered in human narcolepsy with cataplexy and in animal models of this disease.
  
  
  METHODS
  Immunohistochemistry for histidine decarboxylase (HDC) and quantitative microscopy were used to detect histamine cells in human narcoleptics, hypocretin (Hcrt) receptor-2 mutant dogs, and 3 mouse narcolepsy models: Hcrt (orexin) knockouts, ataxin-3-orexin, and doxycycline-controlled-diphtheria-toxin-A-orexin.
  
  
  RESULTS
  We found an average 64% increase in the number of histamine neurons in human narcolepsy with cataplexy, with no overlap between narcoleptics and controls. However, we did not see altered numbers of HDC cells in any of the animal models of narcolepsy.
  
  
  CONCLUSIONS
  Changes in histamine cell numbers are not required for the major symptoms of narcolepsy, because all animal models have these symptoms. The histamine cell changes we saw in humans did not occur in the 4 animal models of Hcrt dysfunction we examined. Therefore, the loss of Hcrt receptor-2, of the Hcrt peptide, or of Hcrt cells is not sufficient to produce these changes. We speculate that the increased histamine cell numbers we see in human narcolepsy may instead be related to the process causing the human disorder. Although research has focused on possible antigens within the Hcrt cells that might trigger their autoimmune destruction, the present findings suggest that the triggering events of human narcolepsy may involve a proliferation of histamine-containing cells. We discuss this and other explanations of the difference between human narcoleptics and animal models of narcolepsy, including therapeutic drug use and species differences.
authors.affiliation: Neurobiology Research, Veterans Administration Greater Los Angeles Healthcare System, Neuropsychiatric Institute and Brain Research Institute, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Joshi
authors.initials: J
authors.lastname: John
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Thannickal
authors.forename: Ronald
authors.initials: R
authors.lastname: McGregor
authors.forename: Lalini
authors.initials: L
authors.lastname: Ramanathan
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohtsu
authors.forename: Seiji
authors.initials: S
authors.lastname: Nishino
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sakai
authors.forename: Akhiro
authors.initials: A
authors.lastname: Yamanaka
authors.forename: Carly
authors.initials: C
authors.lastname: Stone
authors.forename: Marcia
authors.initials: M
authors.lastname: Cornford
authors.forename: Jerome M
authors.initials: JM
authors.lastname: Siegel
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D002385:Cataplexy / Q000378:metabolism*; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009290:Narcolepsy / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*
chemical_list: D006632:Histamine